BW-00112 targeting ANGPTL3 results in prolonged reductions in plasma triglycerides, LDL-C, and remnant-C in Chinese healthy subjects
Bibliographic record
Abstract
Abstract Background/Introduction Dyslipidemia is a significant risk factor for cardiovascular disease (CVD), and a residual risk of CVD remains despite the current standard of care. While combination therapies are often employed, some patients experience safety concerns and adverse side effects. Angiopoietin-like protein 3 (ANGPTL3) has emerged as a promising therapeutic target for the treatment of dyslipidemia. Genome-wide association studies have identified ANGPTL3 as a critical regulator of blood lipid levels in humans. It modulates lipid and lipoprotein metabolism by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL). BW-00112 is a fully synthetic, chemically optimized, double-stranded ANGPTL3 siRNA conjugated with N-acetylgalactosamine (GalNAc) for targeted delivery. This innovative approach shows great potential in addressing unmet needs in the management of dyslipidemia. Purpose The primary objective of this study was to assess the safety and tolerability of a single dose of BW-00112 in Chinese healthy subjects with 100 mg/dL ≤ LDL-C < 190 mg/dL and 100 mg/dL≤ TG <500 mg/dL up to 12 weeks. The secondary objectives of this study were to characterize pharmacokinetics (PK) profile and evaluate the pharmacodynamics (PD) effect (ANGPTL3, TG, LDL-C, non-HDL-C) of a single dose of BW-00112 up to 12 weeks. Methods This was a phase 1, randomized, double-blind, placebo-controlled, single dose study to evaluate the safety, tolerability, PK, and PD of subcutaneous doses of BW-00112 in Chinese healthy subjects with elevated LDL-C who were not receiving lipid-lowering therapy. Results BW-00112 was well tolerated with subcutaneous administration as a single dose ranging from 150 mg to 600 mg in Chinese healthy subjects. There were no serious adverse events, and no death or study discontinuations due to treatment-emergent adverse events (TEAEs). Most of the TEAEs were mild in severity. Adverse events of special interest, including injection site reactions and abnormalities in liver function, did not raise safety concerns. Exposure (AUC0-last and Cmax) increased in a dose-dependent manner within the linear range of 150 mg to 600 mg. However, the increase was slightly more than dose proportional. BW-00112 at doses of 150 mg to 600 mg resulted in substantial reductions in ANGPTL3 levels (mean -76% to -89%) 12 weeks after dosing. BW-00112 at doses of 150 mg to 600 mg also led to reductions in triglyceride (mean -62% to -76%), LDL-C (mean -31% to -34%), ApoB (mean -26% to -31%), Non-HDL-C (mean -32% to -36%), and remnant-C (mean -38% to -41%). Conclusion BW-00112 was generally well tolerated when administered subcutaneously as a single dose ranging from 150 mg to 600 mg. Substantial PD effects were observed with single subcutaneous doses of BW-00112 ranging from 150 mg to 600 mg, including reductions in ANGPTL3, triglycerides, LDL-C, ApoB, non-HDL-C, and remnant-C. No big difference was observed on safety, PK, and PD in Australian and Chinese healthy subjects.Reductions in serum ANGPTL3 and lipids
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".